The approach of studying peptide models of Beta-endorphin that have minimal homology to natural sequences will be used to determine the conformation requirements of peptides for binding to different opiate receptors and eliciting a biological response. A model peptide will be prepared that consists of the [Met5]-enkephalin structure connected to a model amphiphilic Alpha-helical domain consisting of leucine, lysine and glutamine residues via a linking peptide composed of alternating serine and glycine residues. This peptide will be obtained by expression of a chemically synthesized gene coding for a chimeric protein specifically designed to form a stable tertiary structure of which the Beta-endorphin model peptide is an integral part. After purification, the Beta-endorphin model peptide will be enzymatically cleaved from this protein and tested for binding to radiolabelled Delta- and Mu-opiate receptors, opiate activity on the rat vas deferens and analgesic activity upon intracerebral injection of mice. A series of peptides having single and multiple amino acid residue changes from this model peptide will then be prepared by oligonucleotide-directed mutagenesis of the synthetic gene in order to test (1) the length requirements of the hydrophilic linking peptide, (2) the importance of specific features of the hydrophobic domain of the amphiphilic Alpha-helical structure, and (3) the effect of destabilizing the amphiphilic Alpha-helical structure. The rapid development of peptides consisting of naturally-occurring amino acid residues that combine a high selectivity for opiate receptor subtypes with a long biological half life and rapid diffusion to their sites of action should then be possible. In addition, by determining the factors affecting binding affinity versus efficacy, peptide antagonists of selected opiate receptor subtypes might also be developed. Such peptides will have potential clinical uses as analgetics that minimize undesirable side effects, as well as providing pharmacological tools useful in understanding the actions of the opioid peptides in general. The modelling approach used combined with the development of a rational design for chimeric proteins should elucidate fundamental principles of peptide hormone structure-function relationships, protein folding and tertiary structure that will be applicable to other systems.